Lenalidomide  (Synonyms: 来那度胺; CC-5013)

Lenalidomide (CC-5013), a derivative of Thalidomide, acts as molecular glue. Lenalidomide is an orally active immunomodulator. Lenalidomide (CC-5013) is a ligand of ubiquitin E3 ligase cereblon (CRBN), and it causes selective ubiquitination and degradation of two lymphoid transcription factors, IKZF1 and IKZF3, by the CRBN-CRL4 ubiquitin ligase. Lenalidomide (CC-5013) specifically inhibits growth of mature B-cell lymphomas, including multiple myeloma, and induces IL-2 release from T cells^[1][2].

Lenalidomide is potent in stimulating T cell proliferation and IFN-γ and IL-2 production. Lenalidomide has been shown to inhibit production of pro inflammatory cytokines TNF-α, IL-1, IL-6, IL-12 and elevate the production of anti-inflammatory cytokine IL-10 from human PBMCs. Lenalidomide downregulates the production of IL-6 directly and also by inhibiting multiple myeloma (MM) cells and bone marrow stromal cells (BMSC) interaction, which augments the apoptosis of myeloma cells^[2]. Dose-dependent interaction with the CRBN-DDB1 complex is observed with Thalidomide, Lenalidomide and Pomalidomide, with IC₅₀ values of ~30 μM, ~3 μM and ~3 μM, respectively, These reduced CRBN expression cells (U266-CRBN₆₀ and U266-CRBN₇₅) are less responsive than the parental cells to antiproliferative effects Lenalidomide across a dose-response range of 0.01 to 10 μM^[3]. Lenalidomide, a thalidomide analog, functions as a molecular glue between the human E3 ubiquitin ligase cereblon and CKIα is shown to induce the ubiquitination and degradation of this kinase, thus presumably killing leukemic cells by p53 activation^[5].

MCE has not independently confirmed the accuracy of these methods. They are for reference only.

The toxicity of Lenalidomide doses up to 15, 22.5, and 45 mg/kg via IV, IP, and PO routes of administration. Limited by solubility in our PBS dosing vehicle, these maximum achievable Lenalidomide doses are well tolerated with the exception of one mouse death (of four total dosed) at the 15 mg/kg IV dose. Notably, no other toxicities are observed in the study at IV doses of 15 mg/kg (n=3) or 10 mg/kg (n=45) or at any other dose level through IV, IP, and PO routes^[4].

MCE has not independently confirmed the accuracy of these methods. They are for reference only.

259.26

C₁₃H₁₃N₃O₃

191732-72-6

固体

Off-white to light yellow

来那度胺；雷那度胺

Room temperature in continental US; may vary elsewhere.

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• [1]. Krönke J, et al. Lenalidomide induces degradation of IKZF1 and IKZF3. Oncoimmunology. 2014 Jul 3;3(7):e941742.  [Content Brief]

  [2]. Kotla V, et al. Mechanism of action of lenalidomide in hematological malignancies. J Hematol Oncol. 2009 Aug 12;2:36.  [Content Brief]

  [3]. Lopez-Girona A, et al. Cereblon is a direct protein target for immunomodulatory and antiproliferative activities of lenalidomide and pomalidomide. Leukemia. 2012 Nov;26(11):2326-35.  [Content Brief]

  [4]. Rozewski DM, et al. Pharmacokinetics and tissue disposition of lenalidomide in mice. AAPS J. 2012 Dec;14(4):872-82.  [Content Brief]

  [5]. Minzel W, et al. Small Molecules Co-targeting CKIα and the Transcriptional Kinases CDK7/9 Control AML in Preclinical Models. Cell. 2018 Sep 20;175(1):171-185.e25.  [Content Brief]

  [6]. Nagashima, Takeyuki, et al. PHARMACEUTICAL COMPOSITION COMPRISING BICYCLIC NITROGEN-CONTAINING AROMATIC HETEROCYCLIC AMIDE COMPOUND AS ACTIVE INGREDIENT. Patent. 20170360780A1.

  [7]. Omran A, et al. Effects of MRP8, LPS, and lenalidomide on the expressions of TNF-α , brain-enriched, and inflammation-related microRNAs in the primary astrocyte culture. ScientificWorldJournal. 2013 Sep 21;2013:208309.  [Content Brief]